Pharmaceutical solution formulations containing 17-AAG

Abstract

A pharmaceutical solution formulation containing 17-AAG in an amount of up to 15 mg / mL dissolved in a vehicle comprising (i) a first component that is ethanol, in an amount of between about 40 and about 60 volume %; (ii) a second component that is a polyethoxylated castor oil, in an amount of between about 15 to about 50 volume %; and (iii) a third component that is selected from the group consisting of propylene glycol, PEG 300, PEG 400, glycerol, and combinations thereof, in an amount of between about 0 and about 35 volume %.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60 / 570,215, filed May 11, 2004, the disclosure of which is incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to pharmaceutical solution formulations containing 17-allylamino-17-demethoxygeldanamycin (“17-AAG”) and methods for their preparation and use. [0004] 2. Description of Related Art [0005] Geldanamycin belongs to the ansamycin family of natural products, whose members are characterized by a benzenoid nucleus (typically a benzoquinone or hydroquinone nucleus) connected at two meta positions to form a macrolactam. Besides geldanamycin, the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin. [0006] Geldanamycin and its derivatives are the most extensively studied of the ansamycins. Although geldanamycin was originally was identified as a...

AI Technical Summary

Benefits of technology

"The present invention provides an improved solution formulation for 17-AAG, which can be administered intravenously to patients. The formulation comprises a concentration of up to 15 mg / mL of 17-AAG dissolved in a vehicle comprising ethanol, polyethoxylated castor oil, and a third component selected from propylene glycol, PEG 300, PEG 400, glycerol, or combinations thereof. The formulation is prepared by diluting the pharmaceutical solution formulation containing up to 3 mg / mL of 17-AAG with water to a concentration of up to 3 mg / mL. The technical effect of this invention is to provide a more stable and effective solution formulation for the intravenous administration of 17-AAG to patients."

Problems solved by technology

The binding of geldanamycin to Hsp90 disrupts Hsp90-client protein interactions, preventing the client proteins from folding correctly and rendering them susceptible to proteasome-mediated destruction.

However, the hepatotoxicity and poor bioavailability of geldanamycin have lead to its discontinuation as a clinical candidate.

A limitation in the preparation of pharmaceutical formulations containing geldanamycin compounds such as geldanamycin itself and 17-AAG, especially for parenteral administration, is their very poor water solubility, only about 0.1 mg / mL at neutral pH for 17-AAG.

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